Significance of Wild-Type p53 Signaling in Suppressing Apoptosis in Response to Chemical Genotoxic Agents: Impact on Chemotherapy Outcome

Abstract

Our genomes are subject to potentially deleterious alterations resulting from endogenous sources (e.g., cellular metabolism, routine errors in DNA replication and recombination), exogenous sources (e.g., radiation, chemical agents), and medical diagnostic and treatment applications. Genome integrity and cellular homeostasis are maintained through an intricate network of pathways that serve to recognize the DNA damage, activate cell cycle checkpoints and facilitate DNA repair, or eliminate highly injured cells from the proliferating population. The wild-type p53 tumor suppressor and its downstream effector p21^WAF1 (p21) are key regulators of these responses. Although extensively studied for its ability to control cell cycle progression, p21 has emerged as a multifunctional protein capable of downregulating p53, suppressing apoptosis, and orchestrating prolonged growth arrest through stress-induced premature senescence. Studies with solid tumors and solid tumor-derived cell lines have revealed that such growth-arrested cancer cells remain viable, secrete growth-promoting factors, and can give rise to progeny with stem-cell-like properties. This article provides an overview of the mechanisms by which p53 signaling suppresses apoptosis following genotoxic stress, facilitating repair of genomic injury under physiological conditions but having the potential to promote tumor regrowth in response to cancer chemotherapy.

Keywords: DNAJB9; apoptosis; chemical genotoxic agents; multinucleated giant cells; mutational processes; p21WAF1 (CDKN1A); p53 signaling; premature senescence.

Figure 1

A partial schematic of the DNA damage surveillance network illustrating the importance of negative regulation of p53 by p21, DNAJ homolog subfamily B member 9 (DNAJB9), and wild-type p53-induced phosphatase 1 (WIP1) in suppressing apoptosis as discussed in this article. Arrows indicate stimulation and T-shaped lines indicate inhibition. Multiple functions of p21 in the DNA damage surveillance network are indicated.

Figure 2

Examples of genotoxic stress-induced responses associated with cancer cell death or survival depending on context: Activation of caspase 3, induction of stress-induced premature senescence (SIPS), and creation of multinucleated giant cells (MNGCs). SIPS is a genetically-controlled process, mediated by p21 or p16, depending on the p53 status of the cells [6,11]. MNGCs can be created through different routes, including endoreduplication (replication of chromosomes without subsequent cell division) and homotypic cell fusions [11].

Figure 3

Cartoon showing mutational processes that can “scar” the genome during different periods of a person’s life span. The various mutations found in a tumor are grouped into “driver” mutations, which are ongoing and confer selective cancer phenotypes, and “historic” (or passenger) mutations which are far more numerous and hitchhike with driver mutations, but do not appear to be causative of cancer development. For details concerning ionizing radiation and other stimuli, consult [138] and [132,133,134,135], respectively. Adapted from Helleday et al. [135].